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Methylation of deoxyribonucleic acid in the rat by the mushroom poison gyromitrin (1983)

Meier-Bratschi, Annelis ; Carden, Brian M. ; Luethy, Juerg ; [et al.]

s.l. : American Chemical Society

Journal of agricultural and food chemistry 31 (1983), S. 1117-1120

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ISSN: 1520-5118

Source: ACS Legacy Archives

Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Process Engineering, Biotechnology, Nutrition Technology

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1021/jf00119a048

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Interaction of estrone and estradiol with DNA and protein of liver and kidney in rat and hamster in vivo and in vitro (1984)

Caviezel, Max ; Lutz, Werner K. ; Minini, Urs ; [et al.]

Springer

Archives of toxicology 55 (1984), S. 97-103

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ISSN: 1432-0738

Keywords: Estrogen ; Hormone ; Carcinogenesis ; DNA binding ; Protein binding ; Estrone ; Estradiol

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract [6,7-3H] Estrone (E) and [6,7-3H]estradiol-17β (E2) have been synthesized by reduction of 6-dehydroestrone and 6-dehydroestradiol with tritium gas. Tritiated E and E2 were administered by oral gavage to female rats and to male and female hamsters on a dose level of about 300 μg/kg (54 mCi/kg). After 8 h, the liver was excised from the rats; liver and kidneys were taken from the hamsters. DNA was purified either directly from an organ homogenate or via chromatin. The radioactivity in the DNA was expressed in the units of the Covalent Binding Index, CBI = (μmol chemical bound per mol DNA-P)/(mmol chemical administered per kg b.w.). Rat liver DNA isolated via chromatin exhibited the very low values of 0.08 and 0.09 for E and E2, respectively. The respective figures in hamster liver were 0.08 and 0.11 in females and 0.21 and 0.18 in the males. DNA isolated from the kidney revealed a detectable radioactivity only in the female, with values of 0.03 and 0.05 for E and E2, respectively. The values for male hamster kidney were 〈 0.01 for both hormones. The minute radioactivity detectable in the DNA samples does not represent covalent binding to DNA, however, as indicated by two sets of control experiments. (A) Analysis by HPLC of the nucleosides prepared by enzyme digest of liver DNA isolated directly or via chromatin did not reveal any consistent peak which could have been attributed to a nucleoside-steroid adduct. (B) All DNA radioactivity could be due to protein contaminations, because the specific activity of chromatin protein was determined to be more than 3,000 times higher than of DNA. The high affinity of the hormone to protein was also demonstrated by in vitro incubations, where it could be shown that the specific activity of DNA and protein was essentially proportional to the concentration of radiolabelled hormone in the organ homogenate, regardless of whether the animal was treated or whether the hormone was added in vitro to the homogenate. Carcinogens acting by covalent DNA binding can be classified according to potency on the basis of the Covalent Binding Index. Values of 103–104 have been found for potent, 102 for moderate, and 1–10 for weak carcinogens. Since estrone is moderately carcinogenic for the kidney of the male hamster, a CBI of about 100 would be expected. The actually measured limit of detection of 0.01 places covalent DNA binding among the highly unlikely mechanisms of action. Similar considerations can be made for the liver where any true covalent DNA binding must be below a level of 0.01. It is concluded that an observable tumor induction by estrone or estradiol is unlikely to be due to DNA binding.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF00346046

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3

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Tests for mutagenicity in salmonella and covalent binding to DNA and protein in the rat of the riot control agent o-chlorobenzylidene malononitrile (CS) (1981)

Däniken, Albert ; Friederich, Urs ; Lutz, Werner K. ; [et al.]

Springer

Archives of toxicology 49 (1981), S. 15-27

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ISSN: 1432-0738

Keywords: o-Chlorobenzylidene malononitrile ; Riot control agents ; DNA Binding ; Salmonella/microsome assay ; Carcinogens ; Mutagens

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract The aim of this study was to determine whether o-chlorobenzylidene malononitrile (CS) exhibits any genotoxic activity towards Salmonella or mammalian DNA in vivo. CS was synthesized with a [14C]-label at the benzylic carbon atom. It was administered i.p. at a dose level of 13 mg/kg (1 mCi/kg) to young adult male rats. Liver and kidney DNA was isolated after 8,25, and 75 h. The radioactivity was at (liver, 8 and 75 h) or below (all other samples) the limit of detection of 3 dpm. Therefore, a possible binding of CS to DNA is at least 105 times lower than that of the strong hepatocarcinogen aflatoxin B1, and 4,000 times lower than that of vinyl chloride. In contrast to this lack of DNA binding, but in agreement with the chemical reactivity of CS, a binding to nuclear proteins could be detected with specific activities ranging between 50 and 121 dpm/mg for liver and between 3 and 41 dpm/mg for kidney. Protein binding could well be responsible for its pronounced cytotoxic effects. CS was also tested in the Ames Salmonella/microsome assay. Strains TA 1535, TA 1537, TA 1538, TA 98, and TA 100 were used with or without pre-incubation. Only with strain TA 100 and only without pre-incubation, a doubling of the number of revertants was detectable at the highest dose levels used, 1,000 and 2,000 μg CS per plate. With pre-incubation of TA 100 with CS, a slight increase of the number of revertants was seen at 100 and 500 μg per plate, and a subsequent fall below control values at 1,000 μg. A check for the number of surviving bacteria revealed a strong bacteriotoxicity of the higher doses of CS so that the calculated mutation frequencies, i.e., the number of revertants per number of surviving bacteria, increased with doses up to 500 μg. This toxicity could be counteracted in part by the addition of increasing amounts of rat liver microsomes. In the view of these results, and taking into account the rare and low exposure of man, it is concluded that CS will not create a risk for the induction of point mutations or of carcinogenic processes mediated by DNA binding.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF00352067

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4

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Effect of inhalation exposure regimen on DNA binding potency of 1,2-dichloroethane in the rat (1991)

Baertsch, Amadeus ; Lutz, Werner K. ; Schlatter, Christian

Springer

Archives of toxicology 65 (1991), S. 169-176

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ISSN: 1432-0738

Keywords: 1,2-Dichloroethane ; Carcinogens ; DNA binding ; Rat ; Inhalation ; Dose response

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract 1,2-Dichloroethane (DCE) was reported to be carcinogenic in rats in a long-term bioassay using gavage in corn oil (24 and 48 mg/kg/day), but not by inhalation (up to 150–250 ppm, 7 h/day, 5 days/week). The daily dose metabolized was similar in the two experiments. In order to address this discrepancy, the genotoxicity of DCE was investigated in vivo under different exposure conditions. Female F-344 rats (183–188 g) were exposed to [1,2-14C]- DCE in a closed inhalation chamber to either a low, constant concentration (0.3 mg/l=80 ppm for 4 h) or to a peak concentration (up to 18 mg/l=4400 ppm) for a few minutes. After 12 h in the chamber, the dose metabolized under the two conditions was 34 mg/kg and 140 mg/kg. DNA was isolated from liver and lung and was purified to constant specific radioactivity. DNA was enzymatically hydrolyzed to the 3′-nucleotides which were separated by reverse phase HPLC. Most radioactivity eluted without detectable or with little optical density, indicating that the major part of the DNA radioactivity was due to covalent binding of the test compound. The level of DNA adducts was expressed in the dose-normalized units of the Covalent Binding Index, CBI = (μmol adduct per mol DNA nucleotide/mmol DCE per kg body wt. In liver DNA, the different exposure regimens resulted in markedly different CBI values of 1.8 and 69, for “constant-low” and “peak” DCE exposure levels. In the lung, the respective values were 0.9 and 31. It is concluded that the DNA damage by DCE depends upon the concentration-time profile and that the carcinogenic potency determined in the gavage study should not be used for low-level inhalation exposure.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF02307305

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5

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Quantitative evaluation of DNA binding data for risk estimation and for classification of direct and indirect carcinogens (1986)

Lutz, Werner K.

Springer

Journal of cancer research and clinical oncology 112 (1986), S. 85-91

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ISSN: 1432-1335

Keywords: Chemical carcinogenesis ; Mechanism of action ; Quantitative risk assessment ; Genotoxicity ; Dose-response relationship ; Aflatoxin B1 ; Formaldehyde ; Vinyl chloride

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Summary Investigation of covalent DNA binding in vivo provided evidence for whether a test substance can be activated to metabolites able to reach and react with DNA in an intact organism. For a comparison of DNA binding potencies of various compounds tested under different conditions, a normalization of the DNA lesion with respect to the dose is useful. A covalent binding index, CBI=(μmol chemical bound per mol DNA nucleotide)/(mmol chemical administered per kg body weight) can be determined for each compound. Whether covalent DNA binding results in tumor formation is dependent upon additional factors specific to the cell type. Thus far, all compounds which bind covalently to liver DNA in vivo have also proven to be carcinogenic in a long-term study, although the liver was not necessarily the target organ for tumor growth. With appropriate techniques, DNA binding can be determined in a dose range which may be many orders of magnitude below the dose levels required for significant tumor induction in a long-term bioassay. Rat liver DNA binding was proportional to the dose of aflatoxin B1 after oral administration of a dose between 100 μg/kg and 1 ng/kg. The lowest dose was in the range of general human daily exposures. Demonstration of a lack of liver DNA binding (CBI〈0.1) in vivo for a carcinogenic, nonmutagenic compound is a strong indication for an indirect mechanism of carcinogenic action. Carcinogens of this class do not directly produce a change in gene structure or function but disturb a critical biochemical control mechanism, such as protection from oxygen radicals, control of cell division, etc. Ultimately, genetic changes are produced indirectly or accumulate from endogenous genotoxic agents. The question of why compounds which act via indirect mechanisms are more likely to exhibit a nonlinear range in the dose-response curve as opposed to the directly genotoxic agents or processes is discussed.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF00404387

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Possible implications from results of animal studies in human risk estimations for benzene: nonlinear dose-response relationship due to saturation of metabolism (1987)

Grilli, Sandro ; Lutz, Werner K. ; Parodi, Silvio

Springer

Journal of cancer research and clinical oncology 113 (1987), S. 349-358

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ISSN: 1432-1335

Keywords: Benzene ; Risk estimation ; Carcinogenicity ; Genotoxicity ; Metabolism saturation ; Dose-response relationship

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Summary To date, all risk assessment studies on benzene have been based almost exclusively on epidemiological data. We have attempted a more integrated and quantitative evaluation of carcinogenic risk for humans, trying to utilize, in addition to the epidemiological data, all data available, specifically data on metabolism, genotoxicity, and carcinogenicity in small rodents. An integrated evaluation of the globality of the available data seems to suggest a progressive saturation of metabolic capacity both for man and rodents between 10 and 100 ppm. The most susceptible target cells seem to be different in humans (predominant induction of myelogenous leukemia) and small rodents (induction of a wide variety of tumors). Nevertheless, both epidemiological and experimental carcinogenicity data tend to indicate a flattening of the response for the highest dosages, again suggesting a general saturation of mechanisms of metabolic activation, extended to different target tissues. From a quantitative point of view, the data suggest a carcinogenic potency at 10 ppm two to three times higher than that computable by a linear extrapolation from data in the 100 ppm range. These observations are in accord with the recent proposal of the European Economic Community of reducing benzene time-weighted average occupational levels from 10 to 5 ppm.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF00397718

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7

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Stimulation of cell division in the rat by NaCl, KCl, MgCl2, and CaCl2, and inhibition of the sodium chloride effect on the glandular stomach by ascorbic acid and β-carotene (1999)

Lugli, Serena M. ; Lutz, Werner K.

Springer

Journal of cancer research and clinical oncology 125 (1999), S. 209-213

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ISSN: 1432-1335

Keywords: Key words Cell division ; Stomach ; Neoplasms ; Sodium chloride ; Ascorbic acid ; β-carotene

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract Three questions associated with the stimulation of cell division by chloride salts have been investigated: (i) whether cations other than sodium show a similar effect, (ii) whether vitamins can have a preventive activity, and (iii) whether subchronic treatment with sodium chloride in the diet is also effective. Male Fischer 344 rats were given solutions of the chloride salts of sodium, potassium, magnesium, and calcium by oral gavage. Water was used for control. After 4 h, a 24-h osmotic minipump containing 5-bromo-2′-deoxyuridine was implanted subcutaneously. The forestomach and glandular stomach, as well as liver and bladder were analyzed immunohistochemically 24 h later for the proportion of cells in S phase as an indicator of the rate of replicative DNA synthesis. For both the forestomach and the glandular stomach, potassium was as potent as sodium, and the divalent cations Mg and Ca were even more potent on a molar basis. Supplementation of the diet with ascorbic acid (2 g/kg food) or β-carotene (12.5 mg/kg food) for 1 week before gavage of the sodium chloride solution resulted in an inhibition of the stimulation of cell division. A putative tumor-chemopreventive activity of the two vitamins might therefore not only rely on their antioxidative properties but may include effects on the cell cycle. A 4-week treatment with a sodium chloride supplement in the diet (2% and 4% supplement) resulted in a significant stimulation of cell division not only in both parts of the stomach and in the bladder (with the 4% supplement) but also in the liver (even with the 2% supplement). Sodium-chloride-stimulated cell turnover therefore is a sustained effect.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/s004320050264

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Endogenous and exogenous factors in carcinogenesis: limits to cancer prevention (1996)

Lutz, Werner K. ; Fekete, T.

Springer

International archives of occupational and environmental health 68 (1996), S. 120-125

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ISSN: 1432-1246

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract Organ-specific cancer incidence rates can vary dramatically between low- and high-incidence areas. Such differences are due to (1) heritable susceptibility determinants, (2) risk factors associated with the environmental and local living conditions (e.g., viruses, pollution), and (3) personal life-style factors. For organs showing large differences between cancer registries, exogenous factors might be most important, while for organs showing only small differences, endogenous and unavoidable factors are expected to be more important. In this paper, a working hypothesis based on descriptive cancer epidemiology is presented to estimate, in a quantitative manner, the unavoidable contribution to the process of carcinogenesis and to discuss limitations to individual cancer prevention. Cumulative cancer incidence rates for a 75-year period of life (CR74, in percent) were taken from IARC Scientific Publication No. 120 (1992). For each organ, values were ranked in ascending order, and the ratio between high-rate and low-rate registries (90th percentile/10th percentile) was determined. This measure of variability among registries differed strongly between organs. Largest ratios were seen for organs with well-known exogenous risk factors, such as pharynx, lip, tongue, mouth, liver, esophagus, and melanoma in males, and lung, esophagus, gallbladder, liver, and bladder in females. Small ratios were seen for rectum, brain, colon, and Hodgkin's disease in males, and breast, rectum, ovary, brain, and colon in females. It is concluded that the process of carcinogenesis in the latter organs has a stronger endogenous/unavoidable component, for some tissues possibly of hormonal type. A fictitious population was composed where, for each organ, the minimum reported cancer rate was taken. When based on all cancer registries world-wide, CR74 sums over all sites of 2.0% and 2.3% resulted in males and females, respectively. When only Central/Western European countries were included in the analysis in order to reduce differences in risk factors nos, 1 and 2, the sum of the minimum values was 10.4% and 8.7%. After correction of the data for smoking, ‘minimum’ cancer incidence rates in males and females were estimated to be 7.6% and 6.8%. Based on a median cancer incidence rate for nonsmoking males in Europe of about 21%, therefore, individual preventive measures taken by a nonsmoker can reduce the cancer risk, on average, ‘only’ by a factor of about 3. A considerable fraction of cases thus appears to be hardly avoidable.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF00381244

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DNA methylation in the digestive tract of F344 rats during chronic exposure toN-methyl-N-nitrosourea (1991)

Ohgaki, Hiroko ; Ludeke, Barbara I. ; Meier, Irene ; [et al.]

Springer

Journal of cancer research and clinical oncology 117 (1991), S. 13-18

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ISSN: 1432-1335

Keywords: Gastric carcinogenesis ; N-methyl-N-nitrosourea ; DNA methylation

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Summary The formation ofO 6-methyldeoxyguanosine (O 6-MedGuo) was determined by an immuno-slot-blot assay in DNA of various tissues of F344 rats exposed toN-methyl-N-nitrosourea (MNU) in the drinking water at 400 ppm for 2 weeks. Although the pyloric region of the glandular stomach is a target organ under these experimental conditions, the extent of DNA methylation was highest in the forestomach (185 μmolO 6-MedGuo/mol guanine). Fundus (91 μmol/mol guanine) and pylorus (105 μmol/mol guanine) of the glandular stomach, oesophagus (124 μmol/mol guanine) and duodenum (109 μmol/mol guanine) showed lower levels ofO 6-MedGuo but differed little between each other. Thus, no correlation was observed between target organ specificity and the extent of DNA methylation. This is in contrast to the gastric carcinogen,N-methyl-N′-nitro-N-nitrosoguanidine (MNNG), which preferentially alkylates DNA of the pylorus, the main site of induction of gastric carcinomas by this chemical. In contrast to MNU, the non-enzymic decomposition of MNNG is accelerated by thiol compounds (reduced glutathione,l-cysteine), which are present at much higher concentrations in the glandular stomach than in the forestomach and oesophagus. During chronic exposure to MNNG (80 ppm), mucosal cells immunoreactive toO 6-MedGuo are limited to the luminal surface [Kobori et al. (1988) Carcinogenesis 9:2271–2274]. Although MNU (400 ppm) produced similar levels ofO 6-MedGuo in the pylorus, no cells containing methylpurines were detectable by immunohistochemistry, suggesting a more uniform methylation of mucosal cells by MNU than by MNNG. After a single oral dose of MNU (90 mg/kg) cells containing methylpurines were unequivocally identified using antibodies toO 6-MedGuo and the imidazole-ring-opened product of 7-methyldeoxyguanosine. In the gastric fundus, their distribution was similar to those methylated by exposure to MNNG, whereas the pyloric region contained immunoreactive cells also in the deeper mucosal layers. After a 2-week MNU treatment, the rate of cell proliferation, as determined by bromodeoxyuridine immunoreactivity, was only slightly enhanced in the oesophagus and in the fundus, but markedly in the forestomach and the pyloric region of the glandular stomach. It is concluded that the overall extent of DNA methylation, the distribution of alkylated cells within the mucosa and the proliferative response all contribute to the organ-specific carcinogenicity of MNU.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF01613190

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Sorptionseffekte an Metall(III)-hydroxid-Fällungen (1974)

Simon, Jürgen ; Schulze, Werner ; Friedemann, Lutz -Werner

Springer

Fresenius' Zeitschrift für analytische Chemie 268 (1974), S. 185-189

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ISSN: 1618-2650

Keywords: Mitfällung von Mangan(II) mit Aluminiumhydroxid

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Description / Table of Contents: Zusammenfassung Die Mitfällung von Mn2+-Ionen mit gelartigem Al(OH)3 wurde in Abhängigkeit vom pH-Wert und der Mn2+-Konzentration in der überstehenden Lösung untersucht. Für jeweils konstantes pH werden Mitfällungsisothermen erhalten, die formal durch den Langmuirschen Ansatz beschreibbar sind. Die maximal sorbierbare Mn2+-Menge nimmt mit dem pH zu. Zwei lineare Gleichungen beschreiben die Abhängigkeit der Langmuir-Konstanten von der OH−-Konzentration in der Suspension. Es wird daraus gefolgert, daß die Mit-fällung von Mn2+-Ionen eine sekundäre Austauschadsorption ist, die ihre Ursache in der spezifischen Adsorption von OH−-Ionen hat. Die mitgeteilten Gleichungen ermöglichen die quantitative Beschreibung der Mn2+-Sorption in Gegenwart einer definierten K+-Menge als konkurrierendem Kation.

Notes: Abstract The co-precipitation of Mn2+ ions with gelatinous Al(OH)3 was investigated as a function of pH and concentration of Mn2+ in the supernatant solution. For each pH of an acceptable constant value isothermes of co-precipitation were found, obeying formally Langmuir's equation. The maximum quantity of Mn2+, being sorbable, increases in accordance with pH. The functional relationship between Langmuir's constants and the concentration of OH− in the suspension can be expressed by two linear equations. These facts permit co-precipitation of Mn2+ ions to be considered as a counterion-exchange, the reason of which being a specific adsorption of OH− ions. The equations mentioned above allow the Mn2+ sorption to be described quantitatively in presence of a definitive amount of K+ being a competing cation.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF00430602

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